Indenopyridine derivatives

ABSTRACT

Disclosed is a compound of formula (I) 
                         
and salts thereof. Also disclosed are methods of making the compound of formula (I) and the use of the compound as an intermediate for making pharmaceutically active compounds such as 11-β-hydroxysteroid hydrogenase type 1 (11-β-HSD1) inhibitors.

TECHNICAL FIELD

This application relates to indenopyridine derivatives. Theindenopyridine derivatives of the invention are useful as intermediatesfor the preparation of pharmaceutically active compounds such as11-β-hydroxysteroid hydrogenase type 1 (11-β-HSD1) inhibitors.

BACKGROUND OF THE INVENTION

Aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridines arereportedly useful as inhibitors of 11-β-hydroxysteroid hydrogenase type1 (“11-β-HSD1”) and for treatment of disorders associated with 11β-HSD1activity including, for example, diabetes mellitus (e.g., type IIdiabetes), obesity, symptoms of metabolic syndrome, glucose intolerance,hyperglycemica (see, e.g., WO 2011/057054).

The aryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridinescan be prepared, for example, from nitrile-substitutedhexahydroindenopyridines as described in WO 2011/057054. In one methoddescribed in WO 2011/057054, the intermediate(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(A) is allowed to react with 1H-benzoimidazole-5-carboxylic acid (B)followed by reaction with hydrogen chloride to provide the 11-β-HSD1inhibitor(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C) as depicted below:

Methods of preparing the compound of formula (A) described in WO2011/057054 include a 13-step synthesis and a low overall yield (˜2.9%).In addition, some of the described methods utilize corrosive and/ortoxic reagents (e.g., trifluoromethanesulfonic acid anhydride (Tf₂O),boron tribromide (BBr₃) and Zinc cyanide (Zn(CN)₂), which produce aproblematic by-product stream. Thus, there is a need, for improvedprocesses for making compounds of formula (A). Such improvements inmaking intermediate (A) will allow for more efficient preparation ofaryl- and heteroarylcarbonyl derivatives of hexahydroindenopyridinesinhibitors, particularly for large-scale production.

BRIEF SUMMARY OF THE INVENTION

The invention relates to indenopyridine derivatives and salts thereof.In one embodiment, the invention relates to a compound of formula (I):

or a salt thereof.

In another embodiment, the invention relates to a compound of formula(I) in free-base form.

In another embodiment, the invention relates to a salt form of thecompound of formula (I).

In another embodiment, the invention relates to a salt form of thecompound of formula (I), wherein the salt is selected from chloride,bromide, iodide, sulfonate, triflate, and methanesulfonate.

In another embodiment, the invention relates to a compound of formula(II):

In another embodiment, the invention relates to a compound of formula(III):

The invention also relates to a compound of formula (V):

wherein X is selected from chloro, bromo and iodo.

In another embodiment, the invention relates to a compound of formula(V), wherein X is iodo.

In another embodiment, the invention relates to a compound of formula(V), wherein X is bromo.

The invention also relates to methods of making the compounds of formula(I), (II) (III) and (V).

In one embodiment, the invention relates to a method of making thecompound of formula (I), comprising reacting the compound of formula(II) with hydrogen in the presence of a transition metal catalyst toprovide the compound of formula (I).

In another embodiment, the invention relates to a method of making asalt form of the compound of formula (I), comprising

-   -   preparing the compound of formula (I) as described in the        embodiment immediately above, and    -   contacting the compound of formula (I) with a composition        comprising a salt-forming acid to provide the salt of the        compound of formula (I).

In another embodiment, the invention relates to a method of making thecompound of formula (II), comprising contacting the compound of formula(III) with a composition comprising hydrogen chloride and water orsulfuric acid-acetic acid mixture to provide the compound of formula(II).

In another embodiment, the invention relates to a method of making thecompound of formula (III), comprising reacting a compound of formula (V)

with a palladium catalyst to provide the compound of formula (III) whereX is as described above.

In another embodiment, the invention relates to a method of making acompound of formula (III) as described in the embodiment immediatelyabove, wherein X is iodo, bromo or chloro.

In another embodiment, the invention relates to a method of making acompound of formula (III) as described in any of the two embodimentsimmediately above, wherein the palladium catalyst is Pd₂(dba)₃, orPd(OAc)₂.

In another embodiment, the invention relates to a method of making thecompound of formula (V), comprising reacting a compound of formula (IV)

with 2-(phenylsulfonyl)pyridine to provide the compound of formula (V),wherein X is selected from chloro, bromo and iodo.

In another embodiment, the invention relates to a method of making acompound of formula (IV) as described in the embodiment immediatelyabove, wherein X is iodo.

In another embodiment, the invention relates to a method of makingcompound VI or the HCl salt form of the compound of formula (VI)

the process comprising contacting the HCl salt form of the compound offormula (I) with a dehydrating agent in organic solvent to provide theHCl salt form of the compound of formula (VI).

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (VI) as described in theembodiment immediately above, wherein the dehydrating agent is selectedPOCl₃, P₂O₅, and SOCl₂.

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (VI) as described in any of thetwo embodiments immediately above, wherein the agent is POCl₃.

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (VI) as described in any of thethree embodiments immediately above, wherein the organic solvent isselected from dioxane, acetonitrile, toluene, 1,2-dichloroethane, andmethylene chloride.

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (VI) as described in any of thethree embodiments immediately above, wherein the organic solvent isdioxane, acetonitrile, toluene or a mixture of them.

In another embodiment, the invention relates to a method of making thecompound of formula (I), the method comprising,

reacting a compound of formula (IV)

with 2-(phenylsulfonyl)pyridine to provide the compound of formula (V),

reacting the compound of formula (V) with a palladium catalyst toprovide the compound of formula (III),

contacting the compound of formula (III) with a composition comprisinghydrogen chloride and water to provide the compound of formula (II),reacting the compound of formula (II) with hydrogen in the presence of atransition metal catalyst to provide the compound of formula (I), andoptionally contacting the compound of formula (I) with a compositioncomprising a salt-forming acid to provide the salt of the compound offormula (I).wherein X is selected from chloro, bromo and iodo.

Further aspects of the invention are described below.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

-   DBTA=dibenzoyl-D-tartaric-   DMF=dimethylyformamide-   EtOAc=ethyl acetate-   EtOH=ethanol-   i-PrOH=isopropanol-   MeOH=methanol-   NaHMDS=sodium hexamethyldisilazane-   Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)-   POCl₃=phosphoryl chloride-   PPh₃=triphenylphosphine-   P₂O₅=phosphorus pentoxide-   SOCl₂=thionyl chloride-   THF=tetrahydrofuran

As noted above, the subject invention relates to compounds of formula(I), or salts thereof, a compound of formula (II), and methods of makingthe compounds.

As used herein, the term “indenopyridine derivatives” as it relates tothe compounds of formulae (I)-(III) includes both compounds with fullyaromatic ring systems (i.e., the compounds of formulae (II) and (III))and a partially saturated ring system (i.e., the compound of formula(I)).

The present invention provides processes for making intermediate(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(A) and the 11-β-HSD1 inhibitor(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C) with fewer steps and higher yield than the processes described in WO2011/057054. The processes of making compounds (A) and (C) describedherein also advantageously avoid the use of the toxic/corrosivereagents.

The compounds of formula (I) and (II) can be prepared by the methoddepicted in Scheme 1 below:

As depicted in Scheme 1,4aH-indeno[2,1-b]pyridine-1-benzyl-6-carbonitrile (III) is allowed toreact with a hydrogen chloride source, (e.g., aqueous HCl) followed byneutralization with base to provide4aH-indeno[2,1-b]pyridine-1-benzyl-6-carboxamide (II). Compound (II) isthen allowed to react with hydrogen in the presence of a transitionmetal catalyst (e.g., carbon-supported palladium) to provide thecompound of formula (I) followed by treatment with a suitablesalt-forming acid (e.g., hydrochloric acid) to provide the salt form ofthe compound of formula (I).

The compound of formula (III) can be prepared by the method depictedbelow in Scheme 2.

As depicted in Scheme 2, a compound of formula (IV) (where X is chloro,bromo, or iodo) is allowed to react with 2-(phenylsulfonyl)pyridine toprovide the compound of formula (V). The compound of formula (V) is thenallowed to react in the presence of a palladium catalyst (e.g.,Pd₂(dba)₃ or Pd(OAc)₂) with or without a ligand to provide the compoundof formula (III).

Salt forms of the compound of formula (I) may be prepared by reactingthe compound of formula (I) (i.e., the free base form of the compound)with a sufficient amount of the appropriate salt-forming acid in water;in an organic diluent like ether, ethyl acetate, ethanol, isopropanol,or acetonitrile, or a mixture thereof; or with gaseous forms of theacid. Non-limiting examples of salt forms of the compound of formula (I)include chloride, bromide, iodide, sulfate, methanesulfonate,benzenesulfate, and mesyltate.

As further described in the Examples section (see Examples 3-5), thesalt forms of the compound of formula (I) can be reacted with adehydrating agent (e.g., phosphorus oxychloride, phosphorus pentoxide,and thionyl chloride) in organic solvent (e.g., dioxane, acetonitrile,toluene, 1,2-dichloroethane, and methylene chloride) to provide the saltform of 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrilewhich can be resolved using chiral chromatography or by complexing withdibenzoyl-D-tartaric (D-DBTA) acid to provide(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(the compound of formula (C) described above and in WO 2011/057054).

In another embodiment, the invention also relates to a method of making(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½di-benzoyl-d-tartaric acid, the method comprising contacting2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile withdi-benzoyl-d-tartaric acid (D-DTBA) (“the D-DTBA contacting step”) toprovide(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½D-DTBA.

In another embodiment, the invention relates to the method of making4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½di-benzoyl-d-tartaric acid as described in the embodiment immediatelyabove, wherein2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile ispresent in the form of a racemate.

In another embodiment, the invention relates to the method of making4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½di-benzoyl-d-tartaric acid as described in the two embodimentsimmediately above, wherein the molar ratio of D-DTBA to2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile in thecontacting step is from about 0.1 to 2; from about 0.1 to about 1; fromabout 0.2 to about 0.5; or about 0.25.

In another embodiment, the invention relates to the method of making(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½di-benzoyl-d-tartaric acid as described in the two embodimentsimmediately above, wherein the2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile isobtained by contacting the hydrogen chloride salt of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile withbase in aqueous media to obtain2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.

In another embodiment, the invention relates to a method of making(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C), the method comprising:

reacting a HCl salt of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I) saltwith a dehydrating agent to provide the HCl salt of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile:

reacting the HCl salt of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile withbase followed by di-benzoyl-d-tartaric acid to provide(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½D-DTBA:

andreacting(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½D-DTBA with base followed by 1H-benzo[d]imidazole-5-carboxylic acid toprovide the compound of formula (C).

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (C), the method comprising:

dissolving the compound of formula (C) as prepared according to theembodiment immediately above in an alcoholic solvent to provide a firstsolution; and

treating the first solution treated with a second solution of HCl in analcoholic solvent to provide the HCl salt form of the compound offormula (C).

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (C) as described in theembodiment described immediately above, wherein the alcohol solvent isethanol or isopropanol.

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (C) as described in the twoembodiments described immediately above, wherein the alcohol solvent isethanol.

In another embodiment, the invention relates to a method of making theHCl salt form of the compound of formula (C) as described in the twoembodiments described above the embodiment immediately above, whereinthe alcohol solvent is isopropanol.

In another embodiment, the invention relates to a method of making thecompound of formula (I) as described in any of the 5 embodimentsimmediately above, wherein the base is aqueous NaOH and the dehydratingagent is POCl₃.

EXAMPLES Example 1 Preparation of4aH-indeno[2,1-b]pyridine-1-benzyl-6-carboxamide (II)

Step 1. Preparation of 2-(phenylsulfonyl)pyridine

Benzensulfinic sodium salt (21.6 Kg, 131.6 mol) is charged to a reactorand treated with 60 L of a solution of acetic acid and water (3:1vol:vol). The contents of the reactor are mixed and treated with2-chloropyridine (30.0 Kg, 264.2 mol). The contents of the reactor areheated to 90° C. and mixed for 2 hrs. An additional solution ofbenzensulfinic sodium salt (26 Kg, 158.4 mol) in 60 L of aceticacid/water (3:1 vol:vol) is added to the reactor slowly over 5 hourswhile maintaining the contents of the reactor at 90° C. The contents ofthe reactor are mixed at 90° C. for about 8 hours, cooled to 20° C., andtreated with water (150 L). The contents of the reactor are stirred for30 minutes and filtered through a centrifuge filter. The filter cake iscollected, treated with isopropanol (41.4 Kg, 52.4 L), and stirred at60° C. After 30 minutes the mixture is cooled to 10° C. over 2 hours,and further mixed for 1 hour at 10° C. The mixture is filtered and thefilter cake is washed with isopropanol (23.70 Kg, 30 L). The filter cakeis collected and dried overnight at 50° C. to provide2-(phenylsulfonyl)pyridine. Yield: 42.5 Kg, 194 mol; 73%.

Step 2. Preparation of1-benzyl-2-(3-iodo-4-cyano-phenyl)methyl)pyridinium bromide

A reactor containing 3-iodo-4-methylbenzonitrile (3.49 Kg; 14.4 mol) and2-(phenylsulfonyl)pyridine (3.0 Kg, 13.7 mol) is purged with nitrogen.The reactor is then charged with dimethylformamide (17.38 L), stirred atroom temperature for 30 minutes, then cooled to 10° C. The contents ofthe reactor are treated drop-wise with 1 M solution of NaHMDS (sodiumhexamethyldisilazane) in tetrahydrofuran (27.4 liters) over 2 hourswhile keeping the internal temperature below 20° C. The reaction mixtureis then treated with acetic acid (783 mL) while keeping the internaltemperature below 20° C. The reaction mixture is heated to 80° C. andthe THF is removed by distillation. The contents of the reactor are thencooled to 25° C., treated with water (13.69 L) over 30 minutes, treatedwith methyl-tetrahydrofuran (MeTHF) (27.3 L), and stirred for 15 minute.The resulting organic phase is collected, washed with water (2×6.85 L),and concentrated to a minimum stirrable volume. The concentrated mixtureis then treated with acetonitrile (27.4 L) and concentrated underreduced pressure to minimum stirrable volume. The acetonitrile treatmentand concentration is repeated twice. The resulting concentrated mixtureis then treated with dry acetonitrile (8.75 L) and benzylbromide (2.57Kg, 15.5 mol), heated to 80° C., mixed for about 18 hours, and cooled to25° C. The mixture is treated with MeTHF (8.75 L), stirred for about 1hour, and filtered. The resulting filter cake is rinsed with MeTHF anddried for about 18 hours at ˜50° C. to provide1-benzyl-2-(3-iodo-4-cyano-phenyl)methyl)pyridinium bromide. Yield: 5.05Kg, 10.28 mol; 75%.

Step 3. Preparation of 4aH-indeno[2,1-b]pyridine-1-benzyl-6-carbonitrile(III)

A solution of Pd₂(dba)₃ (0.64 Kg, 0.70 mol) in DMF (8.09 Kg) is preparedby charging DMF to a reactor and sparging it with nitrogen for at least15 minutes. Pd₂dba₃ (tris(dibenzylideneacetone)dipalladium(0)) is thencharged to the reactor with stirring, and the resulting solution issparged with nitrogen for at least 15 minutes.

A solution of triphenylphosphine (PPh₃) (0.71 Kg, 2.71 mol) in DMF (8.09Kg) is prepared by charging DMF to a reactor and sparging it withnitrogen for at least 15 minutes. PPh₃ is then charged to the reactorwith stirring, and the resulting solution is sparged with nitrogen forat least 15 minutes.

A solution of 1-benzyl-2-(3-iodo-4-cyano-phenyl)methyl)pyridiniumbromide (33.72 Kg, 68.83 mol) and DMF (111.6 Kg) is treated with1,8-diazabicyclo[5.4.01undec-7-ene (DBU) (31.36 Kg, 206 mol). Theresulting solution is sparged with nitrogen for at least 15 minutes andthen treated with the entire amount of the Pd₂dba₃ stock solutionfollowed by the entire amount of the PPh₃ stock solution. The nitrogensparging is maintained during the addition of the Pd₂dba₃ and PPh₃solutions. The contents of the reactor are then heated to 90-95° C., andthe nitrogen sparging is maintained until the reaction temperaturereaches 70° C. The contents of the reactor are then mixed at 90-95° C.for 12 to 18 hours, cooled to 20-25° C., and treated with water (269.76Kg) while maintaining a reaction temperature of 40° C. The resultingmixture is stirred for at least 1 hour at 20° C. and filtered. Theresulting filter cake is washed with water (2×75 L) and dried for about18 hours at ˜50° C. to provide4aH-indeno[2,1-b]pyridine-1-benzyl-6-carbonitrile (III). Yield: 18.07Kg, 64 mol); 93%.

Step 4. Preparation of 4aH-indeno[2,1-b]pyridine-1-benzyl-6-carboxamide(II)

A stirred mixture of 4aH-indeno[2,1-b]pyridine-1-benzyl-6-carbonitrile(III) (18.78 Kg, 66.5 mol) in 1,4-dioxane (167 L) is treated with water(3.6 L) followed by HCl gas (24.2 Kg, 663 mol) at a flow rate sufficientto maintain a batch temperature of 40° C. The mixture is then heated to45° C., stirred for 24 hours, concentrated under reduced pressure, andtreated with water (36.6 L) at a rate sufficient to maintain a batchtemperature of 40° C. The resulting slurry is further mixed at 40° C.until a solution forms. The contents of the reactor are then treatedwith a 20% NaOH solution (20 Kg) at a rate sufficient to maintain abatch temperature of 40° C. followed by treatment with water (97 Kg)over 1 hour. The resulting slurry is cooled to 20° C., stirred for 2hours, and filtered. The resulting filter cake is rinsed with water(2×20 L) and dried for about 18 hours at 40° C. to provide4aH-indeno[2,1-b]pyridine-1-benzyl-6-carboxamide (II). Yield: 21.05 Kg,62.51 mol; 94%.

Example 2 Preparation of Preparation of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I)

A reactor is charged with 10% Pd/C (3.52 Kg, 50% wet), Na₂CO₃ (0.707Kg), 4aH-indeno[2,1-b]pyridine-1-benzyl-6-carboxamide (8 Kg, 26.7 mol)and MeOH (66 L). The resulting mixture is stirred and inerted 3 timeswith H₂. The reactor is then pressurized with H₂ to 200 PSI, thecontents heated to 80° C., mixed at 80° C. for 20 hours, and cooled to20° C. The mixture is then filtered at ambient temperature through aclosed filter pre-packed with Celite-545 using N₂ pressure. Thehydrogenation reactor is rinsed with MeOH (3×18 L), and the MeOH rinsesfiltered through the Celilte filter. The combined MeOH filtratescontents are then concentrated under reduced pressure to about 10% ofthe initial volume. The resulting residue is treated with isopropanol(SOL) and concentrated under reduced pressure to about 10 L. The residueis cooled to 25° C., treated with 20 L of MeOH, and heated to 50-55° C.to provide2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I) infree-base form.

The HCl salt form2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I) isprepared by treating the mixture above at 50-55° C. with 6N HCl/1-PrOH(4.4 to 4.8 Kg), cooling to 20° C. over about 2 hours, stirring forabout 1 hour, and filtering. The resulting filter cake is rinsed with a1:1 (vol:vol) mixture of isopropyl acetate/MeOH (2×4 L) and dried forabout 18 hours at about 50° C. to provide2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I),hydrogen chloride salt. Yield: 5.73 Kg, 22.7 mol; 85%.

Examples 3-5 describe processes for using the compound of formula (I) asa starting material to prepare the compound of formula (C) described inWO 2011/057054.

Example 3 Preparation of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile,hydrogen chloride salt

A mixture of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I),hydrogen chloride salt (7.5 Kg, 25.2 mol) and dioxane (15 L) is stirredfor 30 minutes at 25° C. and treated with POCl₃ (7.77 Kg, 50.4 mol). Themixture is heated to 80° C. over 1 hour and held at 80° C. for 2 hours.The mixture is cooled to 20-25° C., treated over about 30 minutes with asolution of water (1.376 L, 75.6 mol) in dioxane (30 L), stirred for 30minutes, and treated with additional water (1.376 L, 75.6 mol). Theresulting slurry is stirred at 25° C. for about 18 hours and filtered.The resulting filter cake is washed portion-wise with 3.0 L of 1% H₂O in1,4-dioxane and dried for about 18 hours at ˜50° C. to provide2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (III) inthe form of the hydrogen chloride salt. Yield: 4.73 Kg, 20.16 mol; 80%.

Example 4 Preparation of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C)

Step 1. Preparation of(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½di-benzoyl-d-tartaric acid

A mixture of2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile,hydrogen chloride salt (6.22 Kg, 26.5 mol), water (10 L), MeTHF (31 L)and 50% NaOH (4.4 Kg in 7 liter water) is stirred for 1 hours at 25° C.The resulting organic phase is collected, washed with 10% NaOH solution(4.25 Kg of 50% NaOH+17.2 L H₂O), and washed with 10% NaCl solution(1.42 Kg of 50% NaCl+14 L H₂O). The organic phase is concentrated,treated with acetonitrile (25 L), heated to 50° C., and treated over 4hours with a solution of 15-18% di-benzoyl-d-tartaric acid (1.967 Kg,5.5 mol) in acetonitrile (9.38 L). The reaction mixture is allowed tocool to 20° C. over 4 hours and filtered. The resulting filter cake iswashed portion-wise with EtOH (5 L) and dried under reduced pressure.The filter cake is charged to a reactor and treated with MeOH (5.85 L)and EtOH (15.7 L). The mixture is then heated to 50° C., stirred for 2hours, cooled to 20° C. over 2 hours and filtered. The resulting filtercake is washed portion-wise with EtOH (9 Kg) and dried for about 18hours at 50-60° C. to provide(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½D-DTBA. Yield: 4.49 Kg, 11.93 mol: 45% (based on the amount ofracemate); 90% (based on the amount of the (4aR,9aS) enantiomer in thestarting racemate).

Step 2. Preparation of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile

A reactor is charged with(4aR,9aS)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.½D-DTBA (3.396 Kg 9 mol), dichloromethane (14.4 L) and 2N NaOH (13.5 L),and the resulting biphasic mixture is stirred for 30 minutes. The phasesare allowed to separate, and the resulting organic phase is treated with2N NaOH (4.5 L) and stirred for 10 minutes. The organic phase iscollected, concentrated to about half its original volume, and treatedwith a solution of 1H-benzo[d]imidazole-5-carboxylic acid (1.605 Kg, 9.9mol) in DMF (7.2 liters). The mixture is then distilled to remove anyremaining dichloromethane. The mixture is then treated with1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl)(2.070 Kg, 10.8 mol), hydroxybenzotriazole hydrate (HOBt.H₂O) (1.516 Kg,9.9 mol) and triethylamine (3.1 L). The mixture is warmed to 30° C.,stirred for 2 hours, and treated with dichloromethane (12.6 L) and water(12.6 L). The resulting biphasic mixture is stirred for 30 minutes andallowed to phase separate. The organic layer is collected and theaqueous layer is washed with dichloromethane (7.2 L). The combinedorganic layers is charged to a reactor, treated with 2N NaOH (6.75 L)solution, and stirred for 30 minutes. The mixture is then neutralizedwith 6N HCl (2.07 L) to achieve a pH of 9-10. The resulting organicphase is collected, washed with water (2×10 L), concentrated to about ⅓of its original volume, and treated with EtOAc (9 L). The resultingmixture is distilled to remove any remaining dichloromethane, cooled to25° C., and stirred for 30 minutes. The resulting slurry is filtered,and the filter cake is washed portion-wise with EtOAc (2 L) and driedfor about 18 hours at 50° C. to provide(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C) as an EtOAc solvate. Yield: 2.61 Kg (2.22 Kg after correction forpurity of 85% weight % purity), 6.48 mol; 72%.

Step 3. Preparation of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C), hydrogen chloride salt

A mixture of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C) (4.14 Kg, 12.1 mol) and 200 proof absolute EtOH (13.5 Kg) is heatedto 50° C. and filtered through a pre-heated filter funnel. The warmfiltrate is transferred to a pre-heated reactor and treated with 200proof absolute EtOH (2.07 Kg). The contents of the reactor are stirredand slowly treated over 20 minutes with 0.655 Kg of a 6.34 N HClsolution in EtOH. The contents of the reactor are then seeded with 0.105Kg of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrileHCl (previously made according to the procedure described below inExample 5), and stirred for 2 hours at 50° C. The contents of thereactor are treated at a constant addition rate with 0.72 Kg of a 6.34 NHCl solution in EtOH. The contents of the reactor are cooled to about0-5° C. over 2 hours, stirred for about 4 hours, and filtered. Theresulting filter cake is washed with heptane (5 Kg) and dried for 18hours at ˜50° C. to provide(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(C), as the HCl salt. Yield: 4.12 Kg, 10.9 mol. An X-ray powderdiffraction pattern of the product indicated it was the crystal Form IIdescribed in Example 107 of WO2012061708.

Example 5 Preparation of4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrileHCl seed crystals

The seed crystals used in Step 3 of Example 4 above are preparedaccording to the procedures described for crystal Form II in Example 107of WO2012061708.

A reaction vessel is charged with(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(331.5 g) and isopropanol (331.5 g), and the resulting mixture is heatedat 75° C. until a homogeneous solution is formed. The solution istreated with a 5.12 M solution of HCl in isopropanol (29.7 g) followedby isopropanol (5 g) to rinse the addition vessel. The mixture is thenseeded with a slurry of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrilehydrochloride (crystal form II) (19.88 g) in 30 g of isopropanol. (Theslurry was milled for about 1 hour prior to use.) The vessel containingthe seed slurry was rinsed with isopropanol (20 g) and the rinse addedto the reaction vessel. The reactor contents are aged for 1 hour thentreated over 4 hours with a 5.12 M solution of HCl in isopropanol (171.3g). The mixture is cooled to 0-5° C. over 1 hour and aged at thistemperature for 30 min. The resulting precipitate is collected byfiltration, washed with heptane (0-5° C.), and dried under reducedpressure at 65° C. for 8 hours. Yield: 368.9 g (yield: 95%; correctedfor seed charge).

Crystal form II is also obtained by the following procedure: Crystalform I (150 mg) and absolute ethanol (0.6 mL) are stirred at roomtemperature for one week. The precipitate is separated by filtration,washed with little absolute ethanol and dried at 40° C.

Crystal Form II can also be prepared by the following procedure: Amixture of(4a-R,9a-S)-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile(26.07 g) in 200 proof absolute ethanol (104.30 g) is heated to 50° C.The resulting solution is treated with a solution of 4.587 g of a 6.55 Nsolution of HCl in 200 proof absolute EtOH. The mixture is then seededwith a slurry containing 0.782 g of Form II in 2.823 g EtOH. (The slurrywas milled prior to use.) The reaction mixture is then aged at 50° C.for at least 2 hrs. The mixture is then treated over 2 hours with 5.045g of a 6.55 N solution of HCl in EtOH, cooled to 0° C. over 1 hour, andaged at 0° C. for at least 1 hr. The resulting crystals are collected byfiltration and dried at 70° C. under reduced pressure for at least 12hours to provide the seed crystals.

What is claimed is:
 1. A compound of formula (II):


2. A method of making the compound of formula (II) according to claim 1,comprising contacting a compound of formula (III):

with a composition comprising hydrogen chloride and water or sulfuricacid-acetic acid mixture to provide the compound of formula (II).
 3. Acompound of formula (III):


4. A method of making the compound of formula (III) according to claim3, comprising reacting a compound of formula (V)

with a palladium catalyst to provide the compound of formula (III),wherein X is selected from chloro, bromo and iodo.
 5. The method ofclaim 4, wherein the palladium catalyst is Pd₂(dba)₃ or Pd(OAc)₂.
 6. Acompound of formula (V):

wherein X is selected from chloro, bromo and iodo.
 7. The compound offormula (V) of claim 6, wherein X is iodo.
 8. The compound of formula(V) of claim 6, wherein X is bromo.
 9. A method of making a compound offormula (V) according to claim 6,

comprising reacting a compound of formula (IV)

with 2-(phenylsulfonyl)pyridine to provide the compound of formula (V),wherein X is selected from chloro, bromo and iodo.
 10. The method ofclaim 9, wherein X is iodo.